Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The present invention relates to compositions comprising certain retinoids and vitamin D analogs useful in inducing differentiation and inhibiting undesirable proliferation of cells, such as cancer cells and skin cells. The present invention also relates to methods of using the above compositions in the treatment of diseases and conditions characterized by abnormal cell differentiation and/or cell proliferation.
Abnormal cell differentiation and/or cell differentiation is associated with many conditions and diseases. For instance, hyperproliferation of epithelial cells is associated with psoriasis which causes the skin to shed itself too rapidly, every three to four days. The goal in treating psoriasis is to reduce inflammation and to slow down rapid skin cell division.
U.S. Pat. No. 4,866,048 discloses that certain vitamin D derivatives, in particular calcitriol (1 alpha,25-dihydroxy-vitamin D3 or) and calcipotriol are able to stimulate the differentiation of cells and inhibit excessive cell proliferation, and it has been suggested that these compounds are useful in the treatment of diseases characterized by abnormal cell differentiation and/or cell differentiation such as leukemia, myelofibrosis, psoriasis and acne.
Certain retinoids are also known for their antiproliferative and differentiation activity. For instance, retinol (vitamin A) is an endogenous compound which occurs naturally in the human body and is essential for normal cell differentiation of certain cell types such as epithelial cells. Retinoic acid is believed to be an active derivative of retinol. Thus, retinoic acid is believed to be more effective than retinol and retinyl esters at providing skin benefits.
Natural and synthetic vitamin A derivatives (including retinoic acid) have been used extensively in the treatment of a variety of skin and hyperproliferation disorders. For example, retinoic acid has been employed to treat certain types of leukemia like acute apromyelocytic leukemia as well as a variety of skin conditions such as acne, wrinkles, psoriasis, age spots and discoloration (Vahlquist, A. et al., J. Invest. Dermatol., Vol. 94, Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis C. N. et al., xe2x80x9cPharmacology of Retinols in Skinxe2x80x9d, Vasel, Karger, Vol. 3, (1989), pp.249-252; Lowe, N. J. et al., Vol. 3, (1989), pp. 240-248; PCT Patent Application No. WO 93/19743). Although retinoids have been viewed classically as cancer prevention agents, considerable laboratory evidence supports their testing as antitumor drugs as well (Cancer Treat Rep 1987; 71: 493-515 May, 1987).
It is important to note that while clinical experience with either retinoids or vitamin D derivatives against conditions associated with abnormal cell differentiation and/or cell differentiation has met with certain amount of success in some instances, these compounds have frequently been unable to provide the desired clinical results.
For instance, the synthetic Vitamin D, calcipotriol, or retinoic acid which are available in prescription form are somewhat useful for individuals with localized psoriasis. However, these compound are not very effective on most patients.
Therapeutic regimens for acne involve local and systemic therapies, although the former is indicated in the vast majority of cases. Topical application of a variety of chemical application which include mainly sulfur, resorcinol, salicylic acid, benzoyl peroxide, and retinoic acid are frequently used to treat acne. All the foregoing agents are known as xe2x80x9cpeelingxe2x80x9d or xe2x80x9cdryingxe2x80x9d agents which are believed to exert their therapeutical effect by causing erythema, irritation, and desquamination of the skin to expel comedones. The therapeutic efficacy of these agents, however, is rather variable, and their utility is limited partially because of the irritation caused by their application (see U.S. Pat. No. 3,932,665). Oral formulations of retinoic acid are also used but serious side effects are associated with the oral use of this compound including severe fetal malformation in pregnant women.
The present invention provides compositions comprising certain vitamin D and retinoid compounds which are useful for the treatment of disorders characterized by abnormal cell-proliferation and/or cell-differentiation.
Specifically, the present invention provides a composition comprising a vitamin D analog and a retinoid, wherein:
(a) the vitamin D analog is capable of binding a vitamin D receptor or being converted in vivo into a compound capable of binding a vitamin D receptor; and
(b) the retinoid is selected from the group consisting of retinol in a concentration of at least about 1.0% by weight, a compound in a concentration of at least about 1.0% by weight capable of being converted in vivo into retinol, retinoid D with an alcohol CH2OH terminal side chain, retinoid D with an ester at the terminal side chain, retinoid D with an ether at the terminal side chain, retinoid D with an aldehyde at the terminal side chain, and retinoid D with a carboxylic acid at the terminal side chain, wherein retinoid D with the alcohol CH2OH terminal side chain has the structure: 
wherein the configuration at the 7-, 9-, 11- and 13-position double bonds is independently Z or E and wherein R1 is selected from the group consisting of 
wherein the keto group at the 4-position is free or protected, or is replaced by a thioketone group which is free or protected or is replaced by C1-6-alkylidene group; 
wherein X is selected from the group consisting of hydrogen and C1-6-alkyl and Y is selected from the group consisting of C1-6 -alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino and wherein the absolute configuration at the 4-position is independently R or S; 
wherein X1, Y1 are independently selected from the group consisting of hydrogen, C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino and Z1 is selected from the group consisting of C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino; 
wherein X2 is selected from the group consisting of hydrogen, C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino and Z2 is selected from the group consisting of C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino; 
wherein X3 and Y3 are independently selected from the group consisting of hydrogens, C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino so long as X3 and Y3 are not both hydrogens.
The present inventions also provides methods for treating various conditions associated with abnormal cell proliferation and/or abnormal cell differentiation.
In accordance with the invention, It has been surprisingly discovered that a composition comprising a vitamin D analog and a certain retinoid is useful in treating a subject suffering from a disorder characterized by abnormal cell-proliferation and/or cell-differentiation more effectively than either a composition comprising a vitamin D or the above retinoid or a composition comprising a vitamin D analog with other types of retinoids.
The retinoid used in the composition of the present invention is selected from the group consisting of retinol in a concentration of at least about 1.0% by weight, a compound in a concentration of at least about 1.0% by weight capable of being converted in vivo into retinol, retinoid D with an alcohol CH2OH terminal side chain, retinoid D with an ester at the terminal side chain, retinoid D with an ether at the terminal side chain, retinoid D with an aldehyde at the terminal side chain, and retinoid D with a carboxylic acid at the terminal side chain, wherein retinoid D with the alcohol CH2OH terminal side chain has the structure: 
wherein the configuration at the 7-, 9-, 11- and 13-position double bonds is independently Z or E and wherein R1 is selected from the group consisting of 
wherein the keto group at the 4-position is free or protected, or is replaced by a thioketone group which is free or protected or is replaced by C1-6-alkylidene group; 
wherein X is selected from the group consisting of hydrogen and C1-6-alkyl and Y is selected from the group consisting of C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino and wherein the absolute configuration at the 4-position is independently R or S; 
wherein X1, Y1 are independently selected from the group consisting of hydrogen, C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino and Z1 is selected from the group consisting of C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino; 
wherein X2 is selected from the group consisting of hydrogen, C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino and Z2 is selected from the group consisting of C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino; 
wherein X3 and Y3 are independently selected from the group consisting of hydrogens, C1-6-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C1-6-alkyl substituted amino so long as X3 and Y3 are not both hydrogens.
Preferably, the abnormal cell proliferation treated with the composition of the present invention is associated with cancer cells and more preferably with skin cancer such as melanoma. Also more preferably, the abnormal cell proliferation is associated with cancer cells that can at least partially respond to hormone or retinoid treatment.
The present invention also provides a method of treating a subject suffering from a disorder selected from the group consisting of psoriasis, acne, atopic dermatitis, eczema, rosacea, actinic keratosis, seborrheic dermatitis, and congenital keratinization disorders, in which any composition of the present invention is administered to the subject in need of such treatment. Preferably, the disorder is psoriasis, eczema, or acne.
The present invention further provides a method of treating one or more conditions of the skin selected from the group consisting of dry skin, photodamaged skin, age spots, aged skin, increasing stratum corneum flexibility, wrinkles, fine lines, actinic blemishes, skin dyschromias, and ichthyosis, comprising applying to the skin having said one or more condition any composition of the present invention. Preferably, the skin condition is actinic blemishes or fine wrinkles.
The present invention also provides methods for preventing or treating individuals suffering hair loss such as male pattern baldness or female pattern baldness comprising applying to the affected areas of the skin any composition of the present invention.
The present invention further provides methods for restoring the natural color of gray hair comprising applying to the affected areas of the skin any composition of the present invention.
For the purpose of this invention, treatment of a subject with the composition of the present invention means administering or applying to said subject either together or separately both the vitamin D analog and the retinoid as defined in the composition of the present invention. Thus, the vitamin D analog and the retinoid may be administered or applied together or separately using either the same or different forms of administration or application.
Also, for the purpose of this invention, the term xe2x80x9cvitamin D analogxe2x80x9d is defined as a compound capable of binding a vitamin D receptor (not necessarily all) or being converted in vivo into a compound capable of binding a vitamin D receptor (not necessarily all). The term xe2x80x9cvitamin D analogxe2x80x9d includes but is not limited to vitamin D2 and vitamin D3 derivatives such as cholecalciferol, calcifediol, calcitriol, calcipotriol, ergosterol, ergocalciferol, dihydrotachysterol, 1,25-dihydroxyergocalciferol, 25-hydroxydihydrotachysterol, and the vitamin D analogs disclosed in U.S. Pat. No. 4,866,048. Preferred analogs are cholecalciferol, calcifediol, calcitriol, calcipotriol and the vitamin D analogs disclosed in U.S. Pat. No. 4,866,048. More preferred analogs are cholecalciferol, calcifediol, calcitriol and calcipotriol. Most preferred analogs are calcitriol and calcipotriol.
The concentration of the vitamin D analog may vary from about 0.0001% to about 10% by weight of the total composition of the invention. Preferably, the concentrations employed of vitamin D analogs that can directly bind to the vitamin D receptors, range from about 0.0001% to about 1%, more preferably from about 0.0005% to about 0.05%, still more preferably from about 0.009% to about 0.5%, yet still more preferably from about 0.001 to about 0.008%, and most preferably at about 0.005%.
Preferably, the concentration employed of vitamin D analogs that can be converted in vivo to a compound capable of binding a vitamin D receptor is from about 0.001% to about 10%, more preferably from about 0.01% to about 8%, still more preferably from about 1% to about 6%, and most preferably from about 2% to about 5%.
Retinoid D is preferably 4-oxo-retinoic acid, 4-oxo-retinol, and 4-oxo-retinal, 4-hydroxy-retinol, 4-hydroxy-retinal, 4-oxo-retinyl ester, and 4-hydroxyretinyl ester. The most preferred retinoid is 4-oxo-retinol. Preferably, the concentration of retinoid D in the compositions of the invention ranges from about 0.001% to about 1%, more preferably from about 0.025% to about 0.1%, most preferably about 0.05%.
Also, for the purpose of this invention, the term xe2x80x9cretinolxe2x80x9d includes but is not limited to the following: all-trans-retinol, 13-cis-retinol, 1-cis-retinol, 9-cis-retinol, 3,4-didehydro-retinol. Preferred isomers are all-trans-retinol, 13-cis-retinol, 3,4-didehydro-retinol, and 9-cis-retinol. Most preferred is all-trans-retinol due to its wide commercial availability. The concentration employed of retinol is at least about 0.1%, preferably at least 0.3% by weight of the total weight of the composition. More preferably, the concentration such retinoid is from about at 0.3% to about 20%, more preferably from about 0.5% to about 15%, still more preferably from about 0.5% to about 10%, still more preferably from about 1% to about 10%, still more preferably from about 2% to about 10%, and most preferably about 5%.
The retinoids that can be converted in vivo to retinol include but are not limited to retinyl esters, retinyl-glucoronides, retinal, 3,4-didehydro-retinol. Compounds that are converted spontaneously by isomerization are also included in the compounds of the invention.
Retinyl ester is an ester of retinol and is capable of being converted in vivo into retinol. Retinyl esters suitable for use in the present invention include but are not limited to C1-C30 esters of retinol, preferably C2-C20 esters, and most preferably C2, C3, and C6 esters because they are commonly available. Examples of retinyl, esters include but are not limited to: retinyl palmitate, retinyl formate, retinyl acetate, retinyl propionate, retinyl butyrate, retinyl valerate, retinyl isovalerate, retinyl hexanoate, retinyl heptanoate, retinyl octanoate, retinyl nonanoate, retinyl decanoate, retinyl undecandate, retinyl laurate, retinyl tridecanoate, retinyl myristate, retinyl pentadecanoate, retinyl heptadecanoate, retinyl stearate, retinyl isostearate, retinyl nonadecanoate, retinyl arachidonate, retinyl behenate, retinyl linoleate, and retinyl oleate.
The preferred retinyl esters for use in the present invention are retinyl palmitate, retinyl acetate, retinyl propionate and retinyl linoleate. More preferred retinyl esters are retinyl palmitate and retinyl acetate, the most preferred retinyl ester is retinyl palmitate.
The concentration employed of the retinoid that can be converted in vivo to retinol is at least about 0.1%, preferably at least 0.3% by weight of the total weight of the composition. More preferably, the concentration such retinoid is from about at 0.3% to about 20%, more preferably from about 0.5% to about 15%, still more preferably from about 0.5% to about 10%, still more preferably from about 1% to about 10%, still more preferably from about 2% to about 10%, and most preferably about 5%.
It has also been surprisingly discovered that a composition comprising retinol in a concentration of at least about 1.5% or a compound in a concentration of at least about 1.5% capable of being converted in vivo into retinol is as effective as retinoic acid in treating one or more conditions of the skin selected from the group consisting of dry skin, photodamaged skin, age spots, aged skin, increasing stratum corneum flexibility, wrinkles, fine lines, actinic blemishes, skin dyschromias, ichthyosis and acne. The term xe2x80x9cretinolxe2x80x9d and the compounds capable of being converted into retinol has been defined above. Preferably, for this composition, the concentration employed of retinol or of the compound capable of being converted in vivo into retinol is at least about 1.8%, more preferably at least about 2% by weight of the total weight of the composition. More preferably, the concentration such retinoid is from about at 2% to about 20%, more preferably from about 2% to about 15%, still more preferably from about 2% to about 10%, and most preferably about 5%.
The compositions of the present invention are preferably topical and/or pharmaceutical. They may be in the form of a cream, ointment, and gel. They may also comprise a cosmetically acceptable vehicle to act as a diluent, dispersant or carrier for the active components in the composition, so as to facilitate their distribution when the composition is applied to the skin.
Vehicles other than water can include liquid or solid emollients, solvents, humectants, thickeners and powders. An especially preferred nonaqueous carrier is a polydimethyl siloxane and/or a polydimethyl phenyl siloxane. Silicones of this invention may be those with viscosities ranging anywhere from about 10 to 10,000,000 centistokes at 25xc2x0 C. Especially desirable are mixtures of low and high viscosity silicones. These silicones are available from the General Electric Company under trademarks Vicasil, SE and SF and from the Dow Corning Company under the 200 and 550 Series. Amounts of silicone which can be utilized in the compositions of this invention range anywhere from 5% to 95%, preferably from 25% to 90% by weight of the composition.
The cosmetically acceptable vehicle will usually form from 5% to 99.9%, preferably from 25% to 80% by weight of the emulsion, and can, in the absence of other cosmetic adjuncts, form the balance of the composition.
An oil or oily material may be present in the claimed compositions, together with an emulsifier to provide either a water-in-oil emulsion or an oil-in-water emulsion, depending largely on the average hydrophilic-lipophilic balance (HLB) of the emulsifier employed.
Various types of active ingredients may be present in cosmetic compositions of the present invention. Various types of active ingredients may be present in cosmetic compositions of the present invention. Actives are defined as skin benefit agents other than emollients and other than ingredients that merely improve the physical characteristics of the composition. Although not limited to this category, general examples include sunscreens and tanning agents.
Sunscreens include those materials commonly employed to block ultraviolet light. Illustrative compounds are the derivatives of PABA, cinnamate and salicylate. For example, octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone (also known as oxybenzone) can be used. Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone are commercially available under the trademarks, Parsol MCX and Benzophenone-3, respectively. The exact amount of sunscreen employed in the emulsions can vary depending upon the degree of protection desired from the sun""s UV radiation.
Another preferred optional ingredient is selected from essential fatty acids (EFAs), i.e., those fatty acids which are essential for the plasma membrane formation of all cells (in keratinocytes, EFA deficiency makes cells hyperproliferative). Supplementation of EFA corrects this. EFAs also enhance lipid biosynthesis of epidermis and provide lipids for the barrier formation of the epidermis. The essential fatty acids are preferably chosen from linoleic acid, gamma-linolenic acid, homo-gamma-linolenic acid, columbinic acid, eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, gamma-linolenic acid, timnodonic acid, hexaenoic acid and mixtures thereof.
Emollients are often incorporated into cosmetic compositions of the present invention. Levels of such emollients may range from about 0.5% to about 50%, preferably between about 5% and 30% by weight of the total composition. Emollients may be classified under such general chemical categories as esters, fatty acids and alcohols, polyols and hydrocarbons.
Esters may be mono- or di-esters. Acceptable examples of fatty di-esters include dibutyl adipate, diethyl sebacate, diisopropyl dimerate, and dioctyl succinate. Acceptable branched chain fatty esters include 2-ethyl-hexyl myristate, isopropyl stearate and isostearyl palmitate. Acceptable tribasic acid esters include triisopropyl trilinoleate and trilauryl citrate. Acceptable straight chain fatty esters include lauryl palmitate, myristyl lactate, oleyl eurcate and stearyl oleate. Preferred esters include coco-caprylate/caprate (a blend of coco-caprylate and coco-caprate) , propylene glycol myristyl ether acetate, diisopropyl adipate and cetyl octanoate.
Suitable fatty alcohols and acids include those compounds having from 10 to 20 carbon atoms. Especially preferred are compounds such as cetyl, myristyl, palmitic and stearyl alcohols and acids.
Among the polyols which may serve as emollients are linear and branched chain alkyl polyhydroxyl compounds. For example, propylene glycol, sorbitol and glycerin are preferred. Also useful may be polymeric polyols such as polypropylene glycol and polyethylene glycol. Butylene and propylene glycol are also especially preferred as penetration enhancers.
Exemplary hydrocarbons which may serve as emollients are those having hydrocarbon chains anywhere from 12 to 30 carbon atoms. Specific examples include mineral oil, petroleum jelly, squalene and isoparaffins.
Another category of functional ingredients within the cosmetic compositions of the present invention are thickeners. A thickener will usually be present in amounts anywhere from 0.1 to 20% by weight, preferably from about 0.5% to 10% by weight of the composition. Exemplary thickeners are cross-linked polyacrylate materials available under the trademark Carbopol from the B. F. Goodrich Company. Gums may be employed such as xanthan, carrageenan, gelatin, karaya, pectin and locust beans gum. Under certain circumstances the thickening function may be accomplished by a material also serving as a silicone or emollient. For instance, silicone gums in excess of 10 centistokes and esters such as glycerol stearate have dual functionality.
Powders may be incorporated into the cosmetic composition of the invention. These powders include chalk, talc, Fullers earth, kaolin, starch, smectite clays, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, aluminum starch octenyl succinate and mixtures thereof.
Other adjunct minor components may also be incorporated into the cosmetic compositions. These ingredients may include coloring agents, opacifiers, perfumes and preservatives (e.g., imidazolidinyl urea, dimethyl imidazolidinone and diazolidinyl urea). Amounts of these materials may range anywhere from 0.001% up to 20% by weight of the composition.
The composition according to the invention is intended primarily but not exclusively as a product for topical application to human skin and as a product to modulate cell differentiation. In use, a small quantity of the composition, for example from 1 to 5 ml, is applied to exposed areas of the skin, from a suitable container or applicator and, if necessary, it is then spread over and/or rubbed into the skin using the hand or fingers or a suitable device.
The topical skin treatment composition of the invention can be formulated as a lotion having a viscosity of from 4,000 to 10,000 mPas, a fluid cream having a viscosity of from 10,000 to 20,000 mPas or a cream or a gel having a viscosity of from 20,000 to 100,000 mPas or above. The composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer. For example, a lotion or fluid cream can be packaged in a bottle or a roll-ball applicator, or a capsule, or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation. When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar.
The invention accordingly also provides a closed container containing a cosmetically acceptable composition as herein defined.
The following specific examples further illustrate the invention, but the invention is not limited thereto.